title: Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib.
abstract: OBJECTIVE
  To ascertain the effects of erlotinib on CYP3A, to investigate the amplitude and kinetics of erlotinib-mediated inhibition of seven major CYP isoforms in human liver microsomes (HLMs) for evaluating the magnitude of erlotinib in drug-drug interaction in vivo.
  
  
  METHODS
  The activities of 7 major CYP isoforms (CYP1A2, CYP2A6, CYP3A, CYP2C9, CYP2D6, CYP2C8, and CYP2E1) were assessed in HLMs using HPLC or UFLC analysis. A two-step incubation method was used to examine the time-dependent inhibition of erlotinib on CYP3A.
  
  
  RESULTS
  The activity of CYP2C8 was inhibited with an IC(50) value of 6.17±2.0 μmol/L. Erlotinib stimulated the midazolam 1'-hydroxy reaction, but inhibited the formation of 6β-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substrate-dependent: the IC(50) values for inhibiting testosterone 6β-hydroxylation and nifedipine metabolism were 31.3±8.0 and 20.5±5.3 μmol/L, respectively. Erlotinib also exhibited the time-dependent inhibition on CYP3A, regardless of the probe substrate used: the value of K(I) and k(inact) were 6.3 μmol/L and 0.035 min(-1) for midazolam; 9.0 μmol/L and 0.045 min(-1) for testosterone; and 10.1 μmol/L and 0.058 min(-1) for nifedipine.
  
  
  CONCLUSIONS
  The inhibition of CYP3A by erlotinib was substrate-dependent, while its time-dependent inhibition on CYP3A was substrate-independent. The time-dependent inhibition of CYP3A may be a possible cause of drug-drug interaction, suggesting that attention should be paid to the evaluation of erlotinib's safety, especially in the context of combination therapy.
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China.
authors.forename: Pei-pei
authors.initials: PP
authors.lastname: Dong
authors.forename: Zhong-ze
authors.initials: ZZ
authors.lastname: Fang
authors.forename: Yan-yan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Guang-bo
authors.initials: GB
authors.lastname: Ge
authors.forename: Yu-xi
authors.initials: YX
authors.lastname: Mao
authors.forename: Liang-liang
authors.initials: LL
authors.lastname: Zhu
authors.forename: Yan-qing
authors.initials: YQ
authors.lastname: Qu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Li-ming
authors.initials: LM
authors.lastname: Wang
authors.forename: Chang-xiao
authors.initials: CX
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003577:Cytochrome P-450 Enzyme System; D000069347:Erlotinib Hydrochloride; D051544:Cytochrome P-450 CYP3A